Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines.

OBJECTIVE: To determine the effect of endothelin-1 and endothelin-4 on human monocyte production of cytokines. DESIGN: Previous work from our laboratory has shown that endothelin-1 activates leukocytes. Endothelin-1 and endothelin-3 are principally produced by vascular endothelium. However, epidermal cells in gut mucosa, lung, and kidney produce endothelin-2 and endothelin-4, which differ by a single amino acid. While structurally similar to endothelin-1, endothelin-2 and endothelin-4 may affect gut smooth muscle and other tissues differently. The effect of endothelin-1 and endothelin-4 was examined on monocyte production of interleukins (IL) and neutrophil activation factors. SETTING: A clinically-oriented basic science laboratory in a Veterans Administration Hospital and Medical Center. SUBJECTS: Healthy volunteer adult male/female medical students, researchers, and hospital workers. INTERVENTIONS: Human peripheral blood mononuclear cells were separated on density gradients and cultured in media, with or without the addition of bacterial endotoxin or varying molar concentrations of endothelin-1 and endothelin-4. Supernatants were harvested at 10 mins, and at 1, 6, 12, 24, and 48 hrs, and enzyme-linked immunosorbent assays were performed to determine the presence of tumor necrosis factor-alpha, IL-1 beta, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor. MEASUREMENTS AND MAIN RESULTS: Endothelin-1 and endothelin-4 were potent stimuli for monocyte production of tumor necrosis factor-alpha, IL-8, and granulocyte-macrophage colony-stimulating factor. They also caused IL-1 beta and IL-6 production. CONCLUSIONS: Endothelin-1 and endothelin-4 may activate leukocytes after shock or gut ischemia, resulting in further injury to reperfused tissues and distant injury to lungs and other organs.

Endothelin-1, interleukin-6, and interleukin-8 levels increase in patients with burns.

Endothelin is produced by injured or ischemic endothelium and causes monocyte production of interleukins-6 and 8 in vitro. Endothelin levels increase in patients with burn injuries, and we asked whether interleukin-6 and 8 levels increased in patients with burn injuries concurrently with endothelin. Fourteen patients with more than 20% body surface area burns were resuscitated to maintain urine output of 0.5 to 1.0 ml/kg/hr. Blood was drawn on admission and at 12, 24, and 48 hours. Endothelin was measured by radioimmunoassay, interleukins-6 and 8 were measured by enzyme-linked immunosorbent assay. Endothelin levels increased to 6.1 +/- 2.3 fmol on admission, 5.7 +/- 2.1 at 12 hours, 6.9 +/- 2.7 at 24 hours, and 6.4 +/- 2.7 at 48 hours (vs 0.5 in healthy controls). Interleukin-6 increased to 243 +/- 220 pg/ml on admission, 276 +/- 198 at 12 hours, 400 +/- 282 at 24 hours, and 379 +/- 274 at 48 hours (vs less than 50 in healthy controls). Interleukin-8 increased to 504 +/- 309 pg/ml on admission, 483 +/- 263 at 12 hours, 575 +/- 306 at 24 hours, and 698 +/- 667 at 48 hours (vs less than 50 in controls). Endothelin-1 and interleukin-6 and 8 levels increase in patients with burn injuries. Endothelin-mediated activation of monocytes that cause cytokine production may have clinical relevance in patients with burn injuries.